HPV related head and neck squamous cell cancer (HNSCC) is an HIV associated cancer with an increasing incidence despite antiviral therapies. A major limitation to improving treatment outcomes and survival has been a lack of understanding regarding immunologic mechanisms that allow growth and persistence of this antigenic cancer. We have developed unique in vitro and in vivo model systems using mouse tonsillar epithelial cells that express HPV oncogenes to study progression to invasive malignancy. Our long-term goal is to understand key immunologic mechanisms that permit the development of tolerance to the HPV antigens. The objective of this application is to use a preclinical animal model of HPV tumors to explore novel vaccination approaches against HPV tumor that elicit long-lasting protective immune responses in the face of Treg activity. We hypothesize that Treg cells suppress HPV tumor clearance, but anti-tumor immunity can be restored by severing the dendritic cell paracrine supply of IL-2 to Treg cells. The hypothesis is based on preliminary findings that tumor clearance in our HPV-tumor model of squamous cell carcinoma requires effective CD4+ and CD8+ cell adaptive immunity, that tumor persistence may be associated with active mechanism of immune suppression (e.g., Treg), and that the in vitro function of Treg cells depends on IL-2 from dendritic cells. Using our novel animal model of HPV-tumor of the oral cavity we will explore this hypothesis with the following specific aims. Aim 1: Define the role of Treg cells in the progression of HPV- related oral cancer in immune incompetent and immune competent mice. Aim 2: Determine whether severing the IL-2 paracrine source to Tregs blocks Treg suppression, restores anti-HPV immunity and improves tumor clearance. The knowledge gained from this work should make it possible to refine immunologic methods for the treatment of HPV related HNSCC, an area of considerable unmet medical need, particularly in patients who suffer from complications associated with AIDS. PUBLIC HEALTH RELEVANCE HPV related head and neck squamous cell cancer is an HIV associated cancer. The proposal defines immunologic mechanisms of tolerance that promote growth of HPV associated oral tumors and tests innovative strategies for treatment of established tumor in the context of immune tolerance in a mouse model of HPV related cancer.